Chiral switching

Kobayashi and co-workers reported similar enantioselectivity switch in the bi-nol-yterrbium(III) triflate complex-catalyzed cycloaddition reactions [69] between N-benzylidenebenzylamine N-oxide and 3-crotonoyl-2-oxazolidinone [70]. The reaction in the presence of MS 4 A showed an exclusively high enantioselectivity of 96% ee, while that in the absence of MS 4 A (-50% ee) or in the presence of pyridine N-oxide (-83% ee) had the opposite enantioselectivity (Scheme 7.24). This chirality switch happens generally for the combination of a wide variety of nitrones and dipolarophiles. 

These policy decisions by the FDA were the driving force for chiral switches and the commercial development of chromatographic processes such as simulated moving bed (SMB) technology. Due to technological advances such as SMB and the commercial availability of CSPs in bulk quantities for process-scale purification of enantiopure drugs, the production of many single enantiomers now exists on a commercial scale. 

The evolution of FDA policies continues to be a significant driving force on the global pharmaceutical market. Several pharmaceutical firms have made new discoveries while evaluating enantiopure drugs originally discovered and marketed as race-mates by others. These pharmaceutical firms have merged, or other companies have appropriated portfolios of patents based on chiral switches. Thus, the FDA contin-... 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

The enantioselective hydrogenation of C=N bonds is the least-developed hydrogenation reaction, even though many active ingredients contain chiral amine moieties. The main reason for this situation is that effective catalysts - mainly Ir-diphosphine complexes - have been developed only during the past 10 years [124]. A major incentive for the development of more active catalysts was the chiral switch of metolachlor made in 1997 by Ciba-Geigy [125, 126]. 

Omeprazole and esomeprazole. The two S atoms are chiral centers. Source Agranat I, Caner H, Caldwell J. Putting chirality to work the strategy of chiral switches of drug molecules, Nature Reviews Drug Discovery 1 753-768 (2002). Used with permission.)... 

Metolachlor is the active ingredient of Dual , one of the most important grass herbicides for use in maize and a number of other crops. In 1997, after years of intensive research. Dual Magnum, with a content of approximately 90% (I S)-diastereomers and with the same biological effect at about 65% of the use rate, was introduced into the market. This chiral switch was made possible by the new technical process that is briefly described below. The key step of this new synthesis is the enantioselective hydrogenation of the isolated MEA imine, as depicted in Figure 1.3. 

Hofacker AL, Parquette JR. Dendrimer folding in aqueous media an example of solvent-mediated chirality switching. Angew Chem Int Ed 2005 44 1053-1057, S1053/ 1-S1053/17. 

Blaser, H.-U. The Chiral Switch of (S)-Metolachlor A Personal Account of an Industrial Odyssey in Asymmetric Catalysis. Adv. Synth. Catal. 2002, 344, 17-31. 

Oxidation of TTF and its derivatives induces the transformation from neutral species into cationic ones, namely, cation radicals (TTF +) and dications (TTF2+). Moreover, TTF, TTF +, and TTF2+ exhibit different absorption spectra. Taking these advantages of TTF new TTF-based redox fluorescence switches and chiral switches have been recently reported. 

I. Agranat, H. Caner, and ). Caldwell, Putting chirality to work the strategy of chiral switches, Nat. Rev. Drug Discov. 2002, 1, 753-768. 

C functional chiral switches (FU = Functional Unit), D macromolecular switch and switching of matrix organization. 

Various types of chiral switches based on photochromic molecules, as discussed in this chapter, are schematically summarized in Scheme 2. 

Photochemical bistability is a conditio sine qua non, but a number of other requirements are essential for application of chiral switches in photonic materials or optical devices 11,4,101... 

The geometrical isomers and enantiomers of the overcrowded alkenes 15-18 can readily be separated using chiral HPLC. Recently, an asymmetric synthesis of overcrowded alkenes has been developed, involving chirality transfer from an axial single bond to an axial double bond (Scheme 8).32 This methodology is particularly attractive for preparation of larger quantities of enantiomerically pure chiral switches based on overcrowded alkenes. The orientation of the two xanthylidene moieties is dictated by a binaphthol template. After a coupling step and separation of the diastereomers, the bi-xanthylidene is obtained with 96 % e.e. after removal of the template. 

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